Migraine medicine and method of treating the same without caffeine

ABSTRACT

This invention is a safe and effective composition and method for treating acute migraine attacks using pseudoephedrine, acetaminophen, and other agents in an orally administrated form to alleviate the pain and cluster of symptoms characteristic of migraine attacks such as nausea, photophobia, phonophobia, and functional disabilities as well as the prodrome phase of a migraine attack.

[0001] This application claims priority as a divisional application ofU.S. non-provisional patent application serial no. 09/593,238 (filed onJun. 14, 2000) which relies on the priority of provisional patentapplication Serial Number 60/144,973 which was filed on Jul. 22, 1999.

FIELD OF THE INVENTION

[0002] The present invention relates generally to compositions andmethods used to alleviate the symptoms and pain associated with an acutemigraine attack.

BACKGROUND OF THE INVENTION

[0003] An estimated 24 to 26 million Americans—about 18% of women and 6%of men—suffer from migraine pain and migraine-related symptoms. (StewartW F, Lipton R B, Celetano D D, Reed M L. Prevalence of migraine headachein the United States: relation to age, income, race, and othersociodemographic factors. JAMA 1992; 267:64-69.) Attacks are common,with more than 32% of sufferers experiencing more than four episodes permonth. (Rasmussen B K, Stewart W F. The Epidemiology of Migraine. In:Olesen J, Tfelt-Hansen P, Welch K M A, editors. The Headaches, secondedition, New York, N.Y.: Raven Press; 2000; p. 227-233.)

[0004] Migraine, a heterogeneous disorder, produces a wide spectrum ofpain and associated disabilities, both within and among individualsufferers. The spectrum includes mild pain and no disability inapproximately 5-15% of migraine attacks, moderate to severe pain anddisability in approximately 60-70% of attacks, and incapacitating painand total disability in the remaining approximately 25-35% of attacks.(Stewart W F, Schecter A, Lipton R B. Migraine heterogeneity:disability, pain intensity, and attack frequency and duration. Neurology1994; 44 Suppl 4:S24-S39 and Lipton R B, Stewart W F. Migraine in theUnited States: A review of epidemiology and health care use. Neurology1993; 43 Suppl 3:S6-S10.)

[0005] Recent population-based epidemiological studies in the UnitedStates and elsewhere, have found that most people with migraines are notcurrently consulting a physician for their migraine attacks, and onlyabout one-third have ever been diagnosed by a doctor. (Edmeads J.Findlay H, Tugwell P, Pryse-Phillips W, Nelson R F, Murray T J. Impactfor migraine and tension-type headache on lifestyle, consulting behaviorand medication use: a Canadian population survey. Can J Neurol Sci.1993; 20:131-137; Lipton R B, Stewart W F. Medical consultation formigraine [abstract]. Neurology 1994; 44 Suppl 2:A199; and Rasmussen B K,Jensen R, Olesen J, Impact of migraine on sickness, absence andutilization of medical services: a Danish population study. J EpidemiolCommunity Health 1992; 46:443-446.) The overwhelming majority (95% ofmen and 97% of women) of migraineurs, i.e., individuals who suffer frommigraines, used medication to assuage their pain, although only about28% of the men and 40% of the women have ever used prescriptionmedications. (Lipton R B, Stewart W F, Celentano D D, Reed M L.Undiagnosed migraine: A comparison of symptom-based and physiciandiagnosis. Arch Int Med 1992; 152:1273-1278; and Celentano D D, StewartW F, Lipton R B, Reed M L. Medication use and disability amongmigraineurs: a national probability sample survey. Headache 1992;32:223-228.) More than 90% of migraineurs use nonprescription medicationfor their migraines and the majority use nonprescription medicationsexclusively. (Stang P E, Osterhaus J T, Celentano D D. Migraine:patterns of healthcare use. Neurology 1994; 44 Suppl 4:S47-S55; andEdmeads J, Findlay H, Tugwell P, Pryse-Phillips W, Nelson R F, Murray TJ. Impact for migraine and tension-type headache on lifestyle,consulting behavior and medication use: a Canadian population survey.Can J Neurol Sci. 1993; 20:131-137.)

[0006] Many migraine sufferers use single-agent nonprescriptionanalgesics such as acetaminophen, or aspirin, or non-steroidalanti-inflammatory agents to treat their attacks. (Lipton R B, Newman LC, Solomon S. Over-the-counter medication and the treatment of migraine.Headache 1994; 34:547-548.) In other countries, a number ofnonprescription drugs are specifically approved for migraine pain.(Lipton R B, Newman L C, Solomon S. Over-the-counter medication and thetreatment of migraine. Headache 1994; 34:547-548.) The effectiveness ofself-treatment of a migraine and the effectiveness of most suchnonprescription drugs in relieving or aborting migraine pain and/or thecharacteristic symptoms of a migraine has not been adequately studied inwell-controlled clinical trials. (Lipton R B, Newman L C, Solomon S.Over-the-counter medication and the treatment of migraine. Headache1994; 34:547-548.) Acetaminophen, aspirin, and caffeine are approved forrelief of nonspecific headaches and tension headaches (Migliardi J R,Armellino J J, Friedman M, Gillings D B, Beaver W T. Caffeine as ananalgesic adjuvant in tension headache. Clin Pharmacol Ther 1994;56:576-586), which are clinical and physiologically distinct from amigraine.

[0007] Caffeine is widely consumed and has also been indicated for useto treat asthma, drowsiness, fatigue, lumbar puncture headache, andneonatal apnea. Caffeine is also an analgesic adjuvant for a variety ofpain conditions and has been included in combination with otheranalgesics, ergot alkaloids, and barbiturates in prescriptionformulations for a migraine. (Laska E M, Sunshine A, Mueller F, Elvers WB, Siegel C, Rubin A. Caffeine as an analgesic adjuvant. JAMA 1984;251:1711-1718; Olesen J. A review of current drugs for migraine. JNeurology 1991; 238 Suppl 1:S23-S27; Solomon G D. Therapeutic advancesin migraine. J Clin Pharmacol 1993; 33:200-209; and Sawynok J.Pharmacological rationale for the clinical use of Caffeine. Drugs 1995;49:37-50.) Caffeine itself may act to relieve a migraine. Caffeine hasshown to reduce cerebral blood flow in humans and to be a nonselectiveadenosine receptor antagonist. Reduction of cerebral blood flow may bedue to caffeine inhibition of the adenosine A2 receptor. (Sawynok J.Pharmacological rationale for the clinical use of Caffeine. Drugs 1995;49:37-50.) A2 receptors are on cerebral vascular muscles, and act tocause vasodilation. Hence, their inhibition would have the effect ofvasoconstriction similar to other medications used to abort the migraineheadache.

[0008] Although the symptom pattern varies among migraine sufferers, theseverity of migraine pain justifies a need for vigorous therapy in thegreat majority of cases. Traditional therapy, such as ergotamine,although effective during the prodrome phase of a migraine attack, isknown to become progressively less effective if its administration isdelayed. Ergotamine is frequently combined with caffeine, a knownanalgesic adjuvant, to facilitate absorption of the ergot alkaloid.(Schmidt R, Fanchamps A. Effect of Caffeine on intestinal absorption ofergotamine in man. Eur J Clin Pharmacol 1974; 57:213-216.) However,repeated dosing of ergotamine induces long-lasting and cumulativevasoconstriction, thereby requiring careful instructions and managementof individuals who take oral preparations for migraine attack.

[0009] Because of the cumulative toxicity of ergotamine and itsderivatives, safer therapeutics for the treatment and prophylaxis ofmigraines have been sought. Examples of such ergotamine alternatives areergonovine, propranolol, and methysergide. Significant toxicity,however, also occurs in nearly 40% of the individuals who take theseagents. A prescription anti-migraine medication that is an alternativeto ergotamine and its derivatives is sumatriptan (or sumatriptansuccinate), which is a selective 5-hydroxytryptamine. (Deleu D, HanssensY, Worthing E. Symptomatic and prophylactic treatment of migraine: acritical reappraisal. Clin Neuropharmacol 1998; 21(5):267-279; andStewart W F, Lipton R B, Celentano D D, Reed M L. Prevalence of migraineheadache in the United States: relation to age, income, race, and othersociodemographic factors. JAMA 1992; 267:64-69.) When given early,anti-migraine medications effectively abort the acute symptoms of amigraine attack and the prodrome symptoms. Most of these medications,such as ergotamine, its derivatives, and selective 5-hydroxytryptamineagonists, share the physiological property of causing vasoconstriction.(Deleu D, Hanssens Y, Worthing E. Symptomatic and prophylactic treatmentof migraine: a critical reappraisal. Clin Neuropharmacol 1998;21(5):267-279.)

[0010] Thus, a clear goal in the art is to discover new, safe, nontoxic,and effective anti-migraine drugs and treatments, particularlynonprescription treatment medications that can be self-administeredwithout the need of a medical prescription.

SUMMARY OF THE INVENTION

[0011] The present invention relates to a medicinal composition fortreating individuals afflicted with pre-migraine conditions,migraine-associated symptoms, and/or migraine pain of mild to severeintensity. The medicinal composition comprises at least pseudoephedrineand acetaminophen and is orally administrated.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0012] In general, the migraine condition, with or without aura, has avariety of characteristic features. Migraine attacks are episodic andself-limited. The duration of untreated or unsuccessfully treatedmigraine attacks can be from several hours to several days (e.g., aboutfour hours to about three days). Common pain characteristics ofmigraines include pain in a unilateral location, with a pulsatingquality. Pain is usually of moderate to severe intensity and isaggravated by routine physical activity. One or more of a cluster ofsymptoms is recognized to frequently accompany migraines, namely, nauseaand/or vomiting, photophobia, phonophobia, and functional disability,i.e., difficulty in performing routine work-related and non-work-relatedtasks.

[0013] The prodrome phase of a condition of migraine occurs before auraand before severe or throbbing migraine pain. Frequently duringprodrome, the migraine sufferer experiences mood changes, lethargy, andtiredness. It will also be appreciated that migrainous aura, which isexperienced by about 20% of migraine sufferers, precedes severe migrainepain and throbbing. Aura involves distinctive auditory and visualdistortions, which may involve visual scotomas or even hemianopia andspeech abnormalities, which develop prior to severe migraine pain andthrobbing.

[0014] Medicinal treatment of migraine condition can be done during theprodrome phase, or in the aura phase (when it occurs), which are knownto precede an acute migraine attack and migraine pain. Generally, theacute medicinal treatment is more effective in the prodrome phase.However, most acute medicinal treatments for migraine such as thepresent invention can be administered during the prodrome to abort themigraine attack or during the migraine attack once the migraine pain andits other symptoms have developed in order to reduce or eliminatemigraine pain and its associated symptoms.

[0015] As stated above, the present invention relates to a medicinalcomposition for treating individuals afflicted with pre-migraineconditions, migraine-associated symptoms, and/or migraine pain of mildto severe intensity. The medicinal composition comprises at leastpseudoephedrine and acetaminophen and is orally administrated. Eachcomponent of this medicinal composition must be shown to be safe anduseful in treating the migraine complex, and evidence shows that theingredients of the combination can work synergistically to treat amigraine. For example, one additional component that can be added to themedicinal composition which adds synergistic effect is caffeine.

[0016] The ingredients of the combination medication of pseudoephedrine,acetaminophen, and caffeine act synergistically. Caffeine has been shownto act synergistically with acetaminophen to produce analgesia, (SawynokJ. Pharmacological rationale for the clinical use of Caffeine. Drugs1995; 49:36-50.) and to enhance the action of other medications such asergotamine in relieving acute migraine attacks by increasing itsabsorption. (Schmidt R, Fanchamps A. Effect of Caffeine on intestinalabsorption of ergotamine in man. Eur J Clin Pharmacol 1974; 57:213-216.)

[0017] As stated previously, caffeine itself may act to relieve themigraine. Caffeine has shown to reduce cerebral blood flow in humans andto be a nonselective adenosine receptor antagonist. Reduction ofcerebral blood flow may be due to caffeine inhibition of the adenosineA2 receptor. (Sawynok J. Pharmacological rationale for the clinical useof Caffeine. Drugs 1995; 49:37-50.) A2 receptors are on cerebralvascular muscles, and act to cause vasodilation. Hence, their inhibitionwould have the effect of vasoconstriction similar to other medicationsused to abort the migraine headache.

[0018] The large arteries at the base of the brain and the pia materarteries make up the innervated vascular system of the cerebral vessels,which has a rich adrenergic nerve supply and responds to catecholamines.These vessels would vasoconstrict in response to sympathomimetic drugssuch as pseudoephedrine. The non-innervated vascular system is connectedserially to the first, consisting of parenchymal arteries and terminalhigh resistance arterioles. The newer theories about pathogenesis ofmigraine complex describe that in susceptible individuals triggerfactors set off a series of local and systemic events that initiate bothfocal and generalized manifestation of the migraine. Generally, aninitial vasoconstriction phase occurs locally and predominantly in theunilateral cerebral vessels. This unilateral vasoconstriction isassociated with aura in cases of a classic migraine. Thevasoconstriction is followed by reflex vasodilation due to local anoxia,acidosis, and systemic drop in serotonin. Marked vasodilation withaccumulated vasoactive substances sensitizes the pain receptors in theblood vessels and produces a sterile inflammation. These changes alongwith the vasodilation cause the pain in migraine. (Seymour D. Head PainDiagnosis and Management. Clin Symp 1994; 46(3):2-34.)

[0019] Abortion of a migraine headache is thought to be achieved byvasoconstriction of dilated intracranial and extracranial vessels sincevasodilation is associated with the headache phase. (Seymour D. HeadPain Diagnosis and Management. Clin Symp 1994; 46(3):2-34.; Godsby P J.Mechanism and management of headache. J R Coll Physicians Lond May/June1999; 33(3):228-234; and Sawynok J. Pharmacological rationale for theclinical use of Caffeine. Drugs 1995; 49:37-50.) Vasoconstrictionproduces reduction in blood flow. For example ergotamine and sumatriptanproduce vasoconstriction of cranial blood vessels. (Deleu D, Hanssens Y,Worthing E. Symptomatic and prophylactic treatment of migraine: acritical reappraisal. Clin Neuropharmacol 1998; 21(5):267-279.) Thetermination of the headache is achieved 1) by restoring the loss ofhomeostasis of blood supply to the brain to reduce the sterileinflammation caused by vasodilation and 2) by reducing the vasodilatedvessels closer to a normal state that would directly decrease thesensation of pain in the innervated vessels.

[0020] Caffeine and pseudoephedrine may have a synergistic affect oncerebral vasoconstriction, since pseudoephedrine acts as an agonistdirectly on both alpha and, to the lesser degree, beta-adrenergicreceptors. Activation of alpha-adrenergic receptors on vascular smoothmuscles causes vasoconstriction. (Seymour D. Head Pain Diagnosis andManagement. Clin Symp 1994; 46(3):2-34.)

[0021] Acetaminophen has been routinely used to treat mild to moderatemigraines. (Godsby P J. Mechanism and management of headache. J R CollPhysicians Lond May/June 1999; 33(3):228-234; and Deleu D, Hanssens Y,Worthing E. Symptomatic and prophylactic treatment of migraine: acritical reappraisal. Clin Neuropharmacol 1998; 21(5):267-279.)

[0022] Turning to the present invention and study, a hand full ofmigraine patients were treated privately with the combination ofpseudoephedrine 60 mg and acetaminophen 1000 mg every six (6) hours.These patients reported a reduction of their migraine symptoms such asheadache, nausea, phonophobia, and photophobia in 2 hours aftertreatment, as compared to acetaminophen alone. Most cases of migraineattack were completely aborted after one or two treatments (see Table1). TABLE 1 Severity of Severity of headache headache on a on a scaleOther Relief scale of 1-10 of 1-10 symptoms of other before the afterthe besides symptoms Age Sex medication medication headache acheived 29F 8 Completely Photo All relieved and relieved Phono 34 M 6 CompletelyPhoto, All relieved nausea, relieved and Phono 31 F 9.5 CompletelyPhoto, All relieved nausea, relieved and Phono

[0023] Medication is pseudoephedrine 60 mg and acetaminophen 1000 mg,given once, after one episode of a migraine attack.

[0024] Photo=photophobia.

[0025] Phono=phonophobia.

[0026] Nausea

[0027] Pseudoephedrine has been shown to be effective in treatingmigraine patient's cardiovascular abnormalities. A study was done oncardiovascular reflex response in migraine patients. (Munari L, MilaneriI, Silvani A, Bussone G, Bioardi A. Pharmacologic evaluation ofcardiovascular reflex responses in migraine patients: lack of centralsympathetic modulation. Funct. Neurol. 1989; 4(4):375-378.) Pretreatmentwith 2 mg/kg abolished the effects of lower blood pressure aftersustained handgrip that is seen in migraine patients versus normalpatients. This was statistically significant data (p<0.05). Pretreatmentwith 2 mg/kg abolished effects of increased postural hypotension that isseen in migraine patients versus normal patients. This was statisticallysignificant data (p<0.05).

[0028] The components of this medication are relatively safe and withfew side effects. Each component of this medication has been availableas an over-the-counter medication in the US for other uses than thescope of this invention.

[0029] The uses of the combination pseudoephedrine and acetaminophenhave included treatment of the symptoms associated with common cold,nasal congestion, sinus congestion, and sinus pain symptoms, but notmigraine symptoms. Some examples of the brand names of these types ofmedication are Sudafed® Sinus Maximum, Alka-Seltzer® Plus Cold-SinusMedicine Liqui-Gels, Infants' Tylenol® Cold Decongestant & FeverReducer, and Excedrin® Sinus.

[0030] Acetaminophen has been widely used since the 1950s. Acetaminophenhas been used alone for arthralgia, dental pain, dysmenorrhea, fever,headache, mild pain, myalgia, and osteoarthritis. Although,acetaminophen has been used for migraine pain, it has not been used incombination with pseudoephedrine or pseudoephedrine and caffeine.Acetaminophen has proven to be safe and with very few side effectscompared to the group of NSAID analgesics. (Clissold S P., Pharacetamoland phenacetin. Drugs 1986; 32 Suppl 4:315-321.)

[0031] Also, pseudoephedrine has been widely used and shown to be safeand with few side effects. Pseudoephedrine has been mainly used to treatnasal congestion. (Hughes D T D, Empey D W, Land M. Effects ofpseudoephedrine in man. Journal of Clinical and Hospital Pharmacy 1983;8:315-321.)

[0032] Caffeine is widely consumed and has also been indicated for useto treat asthma, drowsiness, fatigue, lumbar puncture headache, andneonatal apnea.

[0033] The length of time that acetaminophen, pseudoephedrine, andcaffeine have been on the market with relatively few side effects hasdemonstrated their excellent safety profiles.

[0034] The present invention is the medicinal composition for treatmentof migraine complex symptoms. The medicinal composition is an oralmedication of pseudoephedrine and acetaminophen, or pseudoephedrine,acetaminophen, and caffeine. Such oral formulations would be in aliquid, solid, or gelatin (semi-solid) form such as an elixir, pill, orcapsule. Without limiting the scope of the present invention, an oraldosage of the combination medication may, for example, compromise;

EXAMPLE 1

[0035] A single solid or liquid dosage form comprise of pseudoephedrinein an amount of from about 30 mg to about 60 mg, acetaminophen in anamount of from about 200 mg to about 1000 mg, and caffeine in an amountof about 40 mg to about 100 mg; or

EXAMPLE 2

[0036] A single solid or liquid dosage form comprise of pseudoephedrinein an amount of from about 30 mg to about 60 mg, and acetaminophen in anamount of from about 200 mg to about 1000 mg.

[0037] The dosage specified in Examples 1 and 2 can be taken every 6hours by mouth. This dosage is in agreement with the over-the-counterrecommended dosages of the pseudoephedrine, acetaminophen, and caffeine.

[0038] Without limiting the scope of the present invention, in thecomposition of these vehicles to administrate the active medications ofpseudoephedrine and acetaminophen, and pseudoephedrine, acetaminophen,and caffeine, acceptable additives may be added if desired. Theacceptable additives may be in the group of glidants, lubricants,disintegrating agents, coloring agents, and fillers. Examples of theseacceptable additives are pregelatinized starch, magnesium sterate,microcrystalline cellulose, croscarmellose sodium, D&C yellow #10, andcolloidal silicon dioxide.

[0039] In conclusion, the present invention relates generally tocompositions and methods used to alleviate the symptoms and painassociated with acute migraine attacks. More particularly, the presentinvention relates to the use of a combination of pseudoephedrine andacetaminophen with optional caffeine, and is orally administrated fortreating individuals afflicted with pre-migraine conditions,migraine-associated symptoms, and/or migraine pain of mild to severeintensity. The combination pseudoephedrine and acetaminophen withoptional caffeine is a new, effective, and convenient medication totreat acute migraine attacks. Each of the ingredients of thiscombination has been shown to be useful in treating the migrainecomplex. Evidence shows that the ingredients of the medicinalcombination work synergistically to treat migraine.

[0040] While preferred embodiments of the present invention have beendisclosed, it will be appreciated that it is not limited thereto but maybe otherwise embodied with the scope of the following claims.

We claim:
 2. A method for treating migraine pain and the cluster ofsymptoms characteristic of a migraine attack, the symptoms includenausea, photophobia, phonophobia, and/or functional disability,comprising the steps of administering to a human subject a compositioncomprising a combination of pseudoephedrine and acetaminophen in anamount effective to reduce or eliminate the migraine pain and one ormore of said symptoms characteristic of migraine.
 4. The methodaccording to claim 2, wherein two or more of said symptomscharacteristic of migraine are reduced.
 6. The method according to claim2, wherein said composition is administered in a solid oral dosage form.8. The method according to claim 6, wherein said dosage form is selectedfrom the group consisting of tablets, pills, caplets, and capsules. 10.The method according to claim 2, wherein the amount of compositionadministered is effective to reduce the migraine pain and/or two or moreof said symptoms characteristic of migraine.
 12. The method according toclaim 2, wherein the amount of composition administered is effective toreduce the migraine pain and/or three or more of said symptomscharacteristic of migraine.
 14. The method according to claim 2, whereinthe amount of composition administered is effective to reduce themigraine pain and/or all four of said symptoms characteristic ofmigraine.
 16. A method of aborting a migraine attack, wherein themigraine attack is characterized by symptoms including nausea,photophobia, phonophobia, and/or functional disability, comprising thesteps of administering to a human subject during a prodrome phase of themigraine attack a migraine abortive effective amount of a compositioncomprising a combination of pseudoephedrine and acetaminophen.
 18. Amethod for treating migraine pain and nausea characteristic of amigraine attack comprising the steps of administering to a human subjecta composition comprising a combination of pseudoephedrine andacetaminophen in an amount effective to reduce the migraine pain andnausea characteristic of a migraine attack.
 20. A method for treatingmigraine pain and photophobia characteristic of a migraine attackcomprising the steps of administering to a human subject a compositioncomprising a combination of pseudoephedrine and acetaminophen in anamount effective to reduce the migraine pain and photophobiacharacteristic of a migraine attack.
 22. A method for treating migrainepain and phonophobia characteristic of a migraine attack comprising thesteps of administering to a human subject a composition comprising acombination of pseudoephedrine and acetaminophen in an amount effectiveto reduce the migraine pain and phonophobia characteristic of a migraineattack.
 24. A method for treating migraine pain and functionaldisability characteristic of a migraine attack comprising the steps ofadministering to a human subject a composition comprising a combinationof pseudoephedrine and acetaminophen in an amount effective to reducethe migraine pain and functional disability characteristic of migraineattack.
 26. An oral composition according to treat migraine pain andother associated symptoms comprising a medicament component consistingof pseudoephedrine, acetaminophen, and one or more pharmaceuticallyacceptable additives selected from the group consisting of a glidant, alubricant, a disintegrating agent, a filler, and a pigmenting material.28. The method according to claim 6, wherein one solid dosage formcomprises pseudoephedrine in an amount of from about 30 mg to about 60mg, and acetaminophen in an amount of from about 200 mg to about 1000mg.
 31. The method according to claim 28, wherein two solid dosage formsare administered to the human subject about every four to six hours. 34.The method according to claim 2, wherein said composition isadministered in a liquid oral dosage form.
 36. The method according toclaim 34, wherein said dosage form is selected from the group consistingof tablets, pills, caplets, capsules, and elixirs.
 38. The methodaccording to claim 34, wherein one liquid dosage form comprisespseudoephedrine in an amount of from about 30 mg to about 60 mg, andacetaminophen in an amount of from about 200 mg to about 1000 mg. 41.The method according to claim 34, wherein two liquid dosage forms areadministered to the human subject about every four to six hours.
 42. Themethod according to claim 34, wherein the composition is notre-administered to the human subject more frequently than once every sixhours.